scholarly journals Pioglitazone Modulates the Vascular Contractility in Hypertension by Interference with ET-1 Pathway

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Roberto Palacios-Ramírez ◽  
Raquel Hernanz ◽  
Angela Martín ◽  
José V. Pérez-Girón ◽  
María T. Barrús ◽  
...  
Keyword(s):  
Peroxisome Proliferator ◽  
Ros Production ◽  
Vascular Effects ◽  
Spontaneously Hypertensive ◽  
Pparγ Agonist ◽  
Proinflammatory Molecule ◽  
Tp Receptors ◽  
No Bioavailability ◽  
Cox 2 ◽  
Peroxisome Proliferator Activated Receptors

Abstract Endothelin-1 (ET-1) is an important modulator of the vascular tone and a proinflammatory molecule that contributes to the vascular damage observed in hypertension. Peroxisome-proliferator activated receptors-γ (PPARγ) agonists show cardioprotective properties by decreasing inflammatory molecules such as COX-2 and reactive oxygen species (ROS), among others. We investigated the possible modulatory effect of PPARγ activation on the vascular effects of ET-1 in hypertension. In spontaneously hypertensive rats (SHR), but not in normotensive rats, ET-1 enhanced phenylephrine-induced contraction through ETA by a mechanism dependent on activation of TP receptors by COX-2-derived prostacyclin and reduction in NO bioavailability due to enhanced ROS production. In SHR, the PPARγ agonist pioglitazone (2.5 mg/Kg·day, 28 days) reduced the increased ETA levels and increased those of ETB. After pioglitazone treatment of SHR, ET-1 through ETB decreased ROS levels that resulted in increased NO bioavailability and diminished phenylephrine contraction. In vascular smooth muscle cells from SHR, ET-1 increased ROS production through AP-1 and NFκB activation, leading to enhanced COX-2 expression. These effects were blocked by pioglitazone. In summary, in hypertension, pioglitazone shifts the vascular ETA/ETB ratio, reduces ROS/COX-2 activation and increases NO availability; these changes explain the effect of ET-1 decreasing phenylephrine-induced contraction.

scholarly journals PPAR Activation Induces M1 Macrophage Polarization via cPLA2-COX-2 Inhibition, Activating ROS Production againstLeishmania mexicana

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
J. A. Díaz-Gandarilla ◽  
C. Osorio-Trujillo ◽  
V. I. Hernández-Ramírez ◽  
P. Talamás-Rohana
Keyword(s):  
Respiratory Burst ◽  
Macrophage Polarization ◽  
Parasite Burden ◽  
Peroxisome Proliferator ◽  
Ros Production ◽  
Macrophages Polarization ◽  
M1 Macrophage ◽  
Ppar Agonists ◽  
Cox 2 ◽  
Peroxisome Proliferator Activated Receptors

Defence againstLeishmaniadepends upon Th1 inflammatory response and, a major problem in susceptible models, is the turnoff of the leishmanicidal activity of macrophages with IL-10, IL-4, and COX-2 upregulation, as well as immunosuppressive PGE2, all together inhibiting the respiratory burst. Peroxisome proliferator-activated receptors (PPAR) activation is responsible for macrophages polarization onLeishmaniasusceptible models where microbicide functions are deactivated. In this paper, we demonstrated that, at least forL. mexicana, PPAR activation, mainly PPARγ, induced macrophage activation through their polarization towards M1 profile with the increase of microbicide activity against intracellular pathogenL. mexicana. PPAR activation induced IL-10 downregulation, whereas the production of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 remained high. Moreover, PPAR agonists treatment induced the deactivation of cPLA2-COX-2-prostaglandins pathway together with an increase in TLR4 expression, all of whose criteria meet the M1 macrophage profile. Finally, parasite burden, in treated macrophages, was lower than that in infected nontreated macrophages, most probably associated with the increase of respiratory burst in these treated cells. Based on the above data, we conclude that PPAR agonists used in this work induces M1 macrophages polarization via inhibition of cPLA2and the increase of aggressive microbicidal activity via reactive oxygen species (ROS) production.

scholarly journals STRUCTURE-BASED DOCKING STUDIES TOWARD EXPLORING THE POTENTIAL ANTICANCER ACTIVITY OF MORIN AGAINST NON-MELANOMA SKIN CANCER THERAPEUTIC DRUG TARGETS

2018 ◽  
Vol 11 (4) ◽  
pp. 61
Author(s):  
Anjugam C ◽  
Sridevi M ◽  
Gnanendra Ts
Keyword(s):  
Binding Energy ◽  
Anticancer Activity ◽  
Drug Targets ◽  
Docking Studies ◽  
Therapeutic Drug ◽  
Peroxisome Proliferator ◽  
Non Melanoma Skin Cancer ◽  
Cox 2 ◽  
Peroxisome Proliferator Activated Receptors ◽  
In Silico Molecular Docking

 Objective: The purpose of this study is to explore the anticancer activity of morin compound against human cyclooxygenase-2 (COX-2) and peroxisome-proliferator-activated receptors (PPARs) isotypes (PPARα and PPARγ) through in silico molecular docking studies.Methods: The 3D structures of human COX-2 complexed with ibuprofen (PDB ID: 4PH9), PPARα complexed with a synthetic agonist (2S)-2-(4- methoxy-3-{[(pyren-1-yl carbonyl) amino] methyl} benzyl) butanoic acid (PDB ID: 3VI8) and PPARγ complexed indomethacin (PDB ID: 3ADX) were retrieved from protein databank. The cocrystallized sites were considered as binding sites, and the docking with morin compound was performed along with their respective cocrystals for each target and compared their interactions and binding affinities.Results: It is observed that the morin compound exhibited better binding energy of -32.9528 kJ/mol against PPARα followed by COX-2 (binding energy: −18.4311 kJ/mol) and PPARγ (binding energy: −17.4228 kJ/mol) when compared to their cocrystallized ligands.Conclusion: The present study suggests that morin compound might serve as potential alternatives in the prevention of skin cancers by showing better activity against PPARα.

scholarly journals The Effect of Biotinylated PAMAM G3 Dendrimers Conjugated with COX-2 Inhibitor (celecoxib) and PPARγ Agonist (Fmoc-L-Leucine) on Human Normal Fibroblasts, Immortalized Keratinocytes and Glioma Cells in Vitro

Molecules ◽  
2019 ◽  
Vol 24 (20) ◽  
pp. 3801 ◽  
Author(s):  
Łukasz Uram ◽  
Maria Misiorek ◽  
Monika Pichla ◽  
Aleksandra Filipowicz-Rachwał ◽  
Joanna Markowicz ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Treatment Strategies ◽  
Pge2 Production ◽  
Peroxisome Proliferator ◽  
Central Nervous System Tumor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Pparγ Agonist ◽  
Cox 2

Glioblastoma multiforme (GBM) is the most malignant type of central nervous system tumor that is resistant to all currently used forms of therapy. Thus, more effective GBM treatment strategies are being investigated, including combined therapies with drugs that may cross the blood brain barrier (BBB). Another important issue considers the decrease of deleterious side effects of therapy. It has been shown that nanocarrier conjugates with biotin can penetrate BBB. In this study, biotinylated PAMAM G3 dendrimers substituted with the recognized anticancer agents cyclooxygenase-2 (COX-2) inhibitor celecoxib and peroxisome proliferator-activated receptor γ (PPARγ) agonist Fmoc-L-Leucine (G3-BCL) were tested in vitro on human cell lines with different p53 status: glioblastoma (U-118 MG), normal fibroblasts (BJ) and immortalized keratinocytes (HaCaT). G3-BCL penetrated efficiently into the lysosomal and mitochondrial compartments of U-118 MG cells and induced death of U-118 MG cells via apoptosis and inhibited proliferation and migration at low IC50 = 1.25 µM concentration, considerably lower than either drug applied alone. Comparison of the effects of G3-BCL on expression of COX-2 and PPARγ protein and PGE2 production of three different investigated cell line phenotypes revealed that the anti-glioma effect of the conjugate was realized by other mechanisms other than influencing PPAR-γ expression and regardless of p53 cell status, it was dependent on COX-2 protein level and high PGE2 production. Similar G3-BCL cytotoxicity was seen in normal fibroblasts (IC50 = 1.29 µM) and higher resistance in HaCaT cells (IC50 = 4.49 µM). Thus, G3-BCL might be a good candidate for the targeted, local glioma therapy with limited site effects.

scholarly journals Nitrooleic Acid Protects against Cisplatin Nephropathy: Role of COX-2/mPGES-1/PGE2Cascade

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Haiping Wang ◽  
Zhanjun Jia ◽  
Jing Sun ◽  
Liang Xu ◽  
Bing Zhao ◽  
...  
Keyword(s):  
Renal Dysfunction ◽  
Kidney Injury ◽  
Histological Change ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Protective Effects ◽  
Plasma Urea ◽  
Lipid Product ◽  
Cox 2 ◽  
Peroxisome Proliferator Activated Receptors

Nitrooleic acid (OA-NO2) is an endogenous lipid product which has novel signaling properties, particularly the activation of peroxisome proliferator-activated receptors. The current study aimed to evaluate the protective effects of OA-NO2against cisplatin-induced kidney injury in mice. Mice were pretreated with OA-NO2for 48 h before cisplatin administration, and the cisplatin-caused nephrotoxicity was evaluated. After the cisplatin treatment (72 h), the vehicle-treated mice displayed renal dysfunction, as evidenced by the elevated plasma urea and creatinine, which was consistent with the histological damage, such as tubular necrosis, dilation, protein cast, and desquamation of epithelial cells. In contrast, the severity of the renal dysfunction and histological change were reduced in the OA-NO2pretreated mice. The renal COX-2 and mPGES-1 mRNAs and their respective proteins expression, together with the renal PGE2amounts, were induced by the cisplatin treatment, but their initiation was reduced by OA-NO2. Moreover, the circulating TNF-α, renal TNF-α, IL-1β, MCP-1, ICAM-1, and VACAM-1 mRNA levels were higher in the cisplatin-treated mice, compared with the controls, but they were attenuated in the OA-NO2pretreatment group. In summary, the pretreatment with OA-NO2remarkably ameliorated the cisplatin-induced kidney injury in mice, possibly via the inhibition of the inflammatory response, associated with the COX-2/mPGES-1/PGE2cascade.

Low-salt diet increases NO bioavailability and COX-2 vasoconstrictor prostanoid production in spontaneously hypertensive rats

Life Sciences ◽  
2016 ◽  
Vol 145 ◽  
pp. 66-73 ◽  
Author(s):  
T.C. Travaglia ◽  
R.C.M. Berger ◽  
M.B. Luz ◽  
L.B. Furieri ◽  
Junior R.F. Ribeiro ◽  
...  
Keyword(s):  
Spontaneously Hypertensive Rats ◽  
Hypertensive Rats ◽  
Salt Diet ◽  
Spontaneously Hypertensive ◽  
Prostanoid Production ◽  
Low Salt ◽  
No Bioavailability ◽  
Cox 2

scholarly journals Reduced Expression of 11β-Hydroxysteroid Dehydrogenase Type 2 in Preeclamptic Placentas Is Associated With Decreased PPARγ but Increased PPARα Expression

Endocrinology ◽  
2014 ◽  
Vol 155 (1) ◽  
pp. 299-309 ◽  
Author(s):  
Ping He ◽  
Zhaoguang Chen ◽  
Qianqian Sun ◽  
Yuan Li ◽  
Hang Gu ◽  
...  
Keyword(s):  
Protein Expression ◽  
Hydroxysteroid Dehydrogenase ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Pparγ Agonist ◽  
Placental Cells ◽  
Mrna And Protein Expression ◽  
Peroxisome Proliferator Activated Receptors ◽  
Specificity Protein

Placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) is reduced in pregnancies complicated with preeclampsia (PE). Peroxisome proliferator-activated receptors β/δ (PPARβ/δ) have been shown to suppress 11β-HSD2 expression in human placental cells. Our objectives were to investigate whether the reduced 11β-HSD2 expression is associated with the changes in PPARs in PE placentas, and whether PPARα and PPARγ affect 11β-HSD2 expression in placental cells. PPARα and PPARβ/δ mRNA and protein expression was increased, whereas PPARγ mRNA and protein expression was decreased in PE placentas. 11β-HSD2 protein expression was inversely correlated with PPARβ/δ in normal placentas but correlated positively with PPARγ and inversely to PPARα in PE placentas. In cultured placental cells, PPARα agonist inhibited, whereas PPARγ agonist stimulated, 11β-HSD2 mRNA and protein expression and activity in a dose-dependent manner. Knockdown of retinoid X nuclear receptor α (RXRα) resulted in a loss of PPARγ effect but not PPARα effect on11β-HSD2. The PPARα effect remained, but the PPARγ effect was lost in the presence of the translational inhibitor cycloheximide. PPARγ agonist dose-dependently stimulated specificity protein 1 (Sp-1) protein expression. Inhibition or knockdown of Sp-1 resulted in a loss of the effects of PPARα and PPARγ. The Sp-1 protein level was not correlated with 11β-HSD2 and PPARs in normal placentas, whereas Sp-1 expression was correlated with 11β-HSD2, PPARγ, and PPARβ/δ in PE placentas. Our data indicate that 11β-HSD2 expression can be modulated by PPARα and PPARγ in placental trophoblasts through Sp-1. Decreased 11β-HSD2 expression in PE placenta might be associated with decreased PPARγ but increased PPARα expression.

scholarly journals Amelioration of Oxidative Stress and Neuroinflammation by Saroglitazar, A Dual PPARα/γ Agonist in MES Induced Epileptic Rats

2019 ◽  
Vol 12 (04) ◽  
pp. 1985-1991
Author(s):  
Snigdha Rani Panigrahy ◽  
Supriya Pradhan ◽  
Chandra Sekhar Maharana
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Marker ◽  
Immunohistochemical Analysis ◽  
Clonic Seizure ◽  
Peroxisome Proliferator ◽  
Ppar Γ ◽  
Group I ◽  
Cox 2 ◽  
Peroxisome Proliferator Activated Receptors ◽  
Pre Treatment

Oxidative stress and neuroinflammatory process are implicated in pathophysiology of epilepsy as well as epileptogenesis. The α and γ isoform of peroxisome proliferator-activated receptors (PPAR) agonist has been reported to have antioxidant and anti-inflammatory functions. We hypothesized that saroglitazar, a dual PPAR-α and PPAR-γ agonist may ameliorate oxidative stress and neuroinflammatory process in MES induced epileptic rats. A total of 36 rats were randomized to different groups (n=6). Group I served as normal control, while in the remaining groups (group IV, V and VI) animals were pre-treated with saroglitazar for 15 days prior to inducing MES. Group I animals were pre-treated with vehicle and group-III with diazepam (2mg/kg). Epilepsy was induced in rats and time taken for onset of tonic hind limb extension (THLE), duration of THLE, duration of clonic phase and recovery time in seconds were noted. Brain SOD and MDA levels were assessed and immunohistochemical analysis was done to evaluate the expression of inflammatory marker COX-2. Pre-treatment with saroglitazar was effective against tonic clonic seizure in MES treated rats. SOD levels significantly increased and a significant reduction in MDA levels with a remarkable decrease in the uptake of COX-2 antibody were reported. Saroglitazar attenuated MES induced epilepsy and the probable underlying mechanisms are due to the inhibition of oxidative stress and neuroinflammation.

Pioglitazone reduces angiotensin II-induced COX-2 expression through inhibition of ROS production and ET-1 transcription in vascular cells from spontaneously hypertensive rats

2014 ◽  
Vol 306 (11) ◽  
pp. H1582-H1593 ◽  
Author(s):  
Jose V. Pérez-Girón ◽  
Roberto Palacios ◽  
Angela Martín ◽  
Raquel Hernanz ◽  
Andrea Aguado ◽  
...  
Keyword(s):  
Spontaneously Hypertensive Rats ◽  
Mrna Levels ◽  
Ros Production ◽  
Activator Protein 1 ◽  
Ang Ii ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Cox 2 ◽  
Anti Inflammatory

Glitazones have anti-inflammatory properties by interfering with the transcription of proinflammatory genes, such as cyclooxygenase (COX)-2, and with ROS production, which are increased in hypertension. This study analyzed whether pioglitazone modulates COX-2 expression in hypertension by interfering with ROS and endothelin (ET)-1. In vivo, pioglitazone (2.5 mg·kg−1·day−1, 28 days) reduced the greater levels of COX-2, pre-pro-ET-1, and NADPH oxidase (NOX) expression and activity as well as O2·− production found in aortas from spontaneously hypertensive rats (SHRs). ANG II increased COX-2 and pre-pro-ET-1 levels more in cultured vascular smooth muscle cells from hypertensive rats compared with normotensive rats. The ETA receptor antagonist BQ-123 reduced ANG II-induced COX-2 expression in SHR cells. ANG II also increased NOX-1 expression, NOX activity, and superoxide production in SHR cells; the selective NOX-1 inhibitor ML-171 and catalase reduced ANG II-induced COX-2 and ET-1 transcription. ANG II also increased c-Jun transcription and phospho-JNK1/2, phospho-c-Jun, and p65 NF-κB subunit nuclear protein expression. SP-600125 and lactacystin, JNK and NF-κB inhibitors, respectively, reduced ANG II-induced ET-1, COX-2, and NOX-1 levels and NOX activity. Pioglitazone reduced the effects of ANG II on NOX activity, NOX-1, pre-pro-ET-1, COX-2, and c-Jun mRNA levels, JNK activation, and nuclear phospho-c-Jun and p65 expression. In conclusion, ROS production and ET-1 are involved in ANG II-induced COX-2 expression in SHRs, explaining the greater COX-2 expression observed in this strain. Furthermore, pioglitazone inhibits ANG II-induced COX-2 expression likely by interfering with NF-κB and activator protein-1 proinflammatory pathways and downregulating ROS production and ET-1 transcription, thus contributing to the anti-inflammatory properties of glitazones.

scholarly journals Antihypertensive effects of peroxisome proliferator-activated receptor-β/δ activation

2017 ◽  
Vol 312 (2) ◽  
pp. H189-H200 ◽  
Author(s):  
Marta Toral ◽  
Miguel Romero ◽  
Francisco Pérez-Vizcaíno ◽  
Juan Duarte ◽  
Rosario Jiménez
Keyword(s):  
Therapeutic Target ◽  
Spontaneously Hypertensive Rat ◽  
Vascular Inflammation ◽  
Organ Damage ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Spontaneously Hypertensive ◽  
Peroxisome Proliferator Activated Receptors ◽  
Biological Actions

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors, which is composed of three members encoded by distinct genes: PPARα, PPARβ/δ, and PPARγ. The biological actions of PPARα and PPARγ and their potential as a cardiovascular therapeutic target have been extensively reviewed, whereas the biological actions of PPARβ/δ and its effectiveness as a therapeutic target in the treatment of hypertension remain less investigated. Preclinical studies suggest that pharmacological PPARβ/δ activation induces antihypertensive effects in direct [spontaneously hypertensive rat (SHR), ANG II, and DOCA-salt] and indirect (dyslipemic and gestational) models of hypertension, associated with end-organ damage protection. This review summarizes mechanistic insights into the antihypertensive effects of PPARβ/δ activators, including molecular and functional mechanisms. Pharmacological PPARβ/δ activation induces genomic actions including the increase of regulators of G protein-coupled signaling (RGS), acute nongenomic vasodilator effects, as well as the ability to improve the endothelial dysfunction, reduce vascular inflammation, vasoconstrictor responses, and sympathetic outflow from central nervous system. Evidence from clinical trials is also examined. These preclinical and clinical outcomes of PPARβ/δ ligands may provide a basis for the development of therapies in combating hypertension.

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